Progress in Autism Translational Research is Being Delayed by Unreliable Animal Models, Says New Paper in Biological Psychiatry

Progress in understanding and treating Autism Spectrum Disorders (ASD) is being delayed due to unreliable animal models and would benefit from increasing replacement with state-of-the-art research techniques like "diseases in a dish," says leading autism neuroscientist Professor Alysson Muotri, ahead of World Autism Awareness Day on 2 April.

ASD is a major global health concern, yet, despite more than 40 years of research dominated recently by artificially creating symptoms in genetically modified mice and other animals in the laboratory, no effective treatments and no cure have been discovered. In a paper in the journal Biological Psychiatry, Muotri explains that recent developments in 21stcentury technologies—such as genetic sequencing of patient tissues and advanced human brain cell cultures - offer a unique opportunity to unravel the underlying pathology of ASD in a relevant human model.

Muotri said: “Autism is a multifactorial human condition and extremely difficult to replicate in a mouse or a monkey to any meaningful degree. To accelerate progress in tackling autism, it’s time for a paradigm shift in the way we research the disorder, and that means investing in 21st-century, human biology-based models and tools.

“With animal research we’re studying an already highly genetically variable disease through the obscured lens of a mouse’s biological, neurological and genetic make-up, with all the species-specific differences that entails in terms of disease physiology and response to drugs. So while we can re-create in mice a few symptoms reminiscent of autism, as a model of the human disease it’s unsatisfactory.

“Now, though, thanks to recent scientific advances, we can study the condition in the right species—humans—and the hope of personalised medicines developed for the specific form of ASD affecting each patient becomes a very real possibility. That would take autism research to the next level, and quite possibly advance the pace of medical progress way beyond anything we’ve seen in the last four decades.”

Muotri is leading a ground-breaking study at the University of California called the “Tooth Fairy Project,” extracting stem cells from baby teeth donated by families of autistic children and re-programming them into fully functioning brain cells (neurons) that can be studied in the laboratory. These brain cells display the specific abnormalities relevant to each child, potentially leading to targeted treatments tailored to the specific autistic pathology of each patient. The Tooth Fairy Project now has more than 3,500 ASD families taking part, and genetic sequencing has already identified five novel human genes that are associated with autism.

If this research continues to progress, Muotri foresees breakthroughs in understanding the most common forms of autism. This would happen by uncovering the molecular and cellular pathways in human brain cells that overlap many types of autism, and thereby discovering novel targets for drug development. In ASD this is needed, as the underlying genetic and environmental causes of the disease remain unknown.

Muotri describes other state-of-the-art developments in science and bioengineering that are transforming the brain research landscape. These include three-dimensional human "mini-brain" models on microchips and the generation of human neuronal microcircuits in cell culture. These advanced cell models will facilitate functional studies of human cerebral cortex development, disease modelling and drug discovery.

Humane Society International is a leading organisation advancing the development of human biology-based approaches in toxicology and bioscience research. Dr. Gill Langley, a physiologist, neurologist and senior science adviser to HSI, said: “We owe it to ourselves to improve the success of medical research across the board, and that means modernising the research paradigm. The conceptual framework of research needs a fundamental re-think: moving beyond outdated and contrived/artificial animal models and prioritizing funding advanced, human biology-based technologies that are directly relevant to human beings. The application of 21st century thinking is already revolutionizing our approach to chemical and product safety testing, and could have the same far-reaching benefits if rigorously applied in the area of disease research.”

Facts:

Autism Spectrum Disorder is a serious, lifelong developmental disorder. Symptoms can include difficulties in communicating and socializing, stereotyped behaviours.

Animal models often do not recapitulate more than a few aspects of complex human diseases, if at all, and this has been particularly problematic in the case of ASDs. The lack of ASD-like behaviours in several knockout mouse models reflects the inherent species differences between mouse and human genetic backgrounds, immune systems and neural circuits. While multiple genetic mutations disrupt social behaviour in mice, the vast majority do not appear to have direct relevance to ASDs. Conversely, many ASD mutations found in patients have no effect in mice or lead to symptoms that do not mimic the human disease.

With a relatively closer evolutionary relationship to humans than inbred mice, non-human primates are also used in an attempt to understand ASD. Recent efforts have included inserting a mutated gene (found in some forms of ASD) into macaque monkeys. Mechanistic insights have not yet emerged from these new animal experiments, but even if they do, the results may be unhelpful because the way the human brain controls gene expression has unique elements not found in any other species.

The work in the Muotri lab is supported by grants from the California Institute for Regenerative Medicine, the National Institutes of Health, the International Rett Syndrome Foundation and Humane Society International.

Alysson Muotri is Associate Professor of Pediatrics/Cellular and Molecular Medicine at the University of California San Diego. Dr. Muotri earned a BSc in Biological Sciences from the State University of Campinas in 1995 and a Ph.D. in Genetics in 2001 from University of Sao Paulo, in Brazil. He moved to the Salk Institute as Pew Latin America Fellow in 2002 for a postdoctoral training in the fields of neuroscience and stem cell biology. He has been a Professor at University of California San Diego since 2008. Dr. Muotri’s lab is interested in modeling neurological diseases, such as Autism Spectrum Disorders, using human induced pluripotent stem cells. His lab has developed several techniques to culture human neurons and glia for basic research and drug-screening platforms. He has received several awards, including the prestigious NIH Director’s New Innovator Award, NARSAD and the Emerald Foundation Young Investigator Award.

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